Anti-thrombotic diazabicyclooctanediones

ABSTRACT

Compounds of the general formula ##STR1## [wherein X represents a sulphur atom (--S--) or oxygen atom (--O--) in the α or β-configuration; 
     X 1  represents a C 1-5  straight chain or branched alkylene group or C 3-5  straight chain or branched alkenylene group; 
     X 2  represents a carboxyl, carboxamide, hydroxymethlene, alkoxycarbonyl or 5-tetrazolyl group; 
     Z represents a hydrogen atom or a C 1-4  straight chain or branched alkyl group; 
     Y represents a group of formula --CR 2  -CH 2  -- in which each R is independently selected from hydrogen and methyl; 
     Y 1  represents a methylene group substituted by hydroxyl, a methylene group substituted by hydroxyl and alkyl, a methylene group or carbonyl group, and 
     Y 2  represents a C 1-7  straight chain or branched alkyl group, phenyl, benzyl or a C 4-7  cycloalkyl group] and salts of those compounds of formula (I) wherein X 2  represents a carboxyl group and/or wherein Z represents a hydrogen atom. 
     These compounds have anti-aggregatory effect on blood platelets and are useful in the treatment or prophylaxis of thrombo-embolic disorders. Processes for the preparation of the compounds are described.

This invention relates to novel diazabicycloctanedione derivatives.

2,4-Diazabicyclo[3.3.0]octane-3,7-dione derivatives, defined below informula (I), have been found to have pharmacological properties relatedto those of natural prostaglandins, as demonstrated by their ability tomimic or antagonise the physiological effects of the naturalprostaglandins in various biological preparations.

Thus, according to one feature of the present invention we providecompounds of the general formula ##STR2## X represents a sulphur atom(--S--) or oxygen atom (--O--) in the α- or β-configuration;

X¹ represents a C₁₋₅ straight chain or branched alkylene group or C₃₋₅straight chain or branched alkenylene group;

X² represents a carboxyl, carboxamide, hydroxymethylene, alkoxycarbonylor 5-tetrazolyl group;

Z represents a hydrogen atom or a C₁₋₄ straight chain or branched alkylgroup;

Y represents a group of formula --CR₂ --CH₂ -- in which each R isindependently selected from hydrogen and methyl;

Y¹ represents a methylene group substituted by hydroxyl, a methylenegroup substituted by hydroxyl and alkyl, a methylene group or a carbonylgroup, and

Y² represents a C₁₋₇ straight chain or branched alkyl group, phenyl,benzyl or a C₄₋₇ cycloalkyl group. Included in the meaning of thecompounds of formula (I) are the salts of those compounds in formula (I)wherein X² represents a carboxyl group and also the salts which may beformed when Z is hydrogen.

Preferred compounds of formula (I) include those wherein X represents asulphur atom, for example in the β-configuration, and X² represents acarboxyl group. X¹ advantageously represents a straight chain propylenegroup. Z is preferably a hydrogen atom. In the 2-position side chain Yis preferably a --CH₂ --CH₂ --group and Y¹ is preferably a methylenegroup substituted by hydroxyl (the hydroxyl substituted preferably beingin the β-configuration). Y² is preferably a C₄₋₆ straight chain orbranched alkyl group (particularly a pentyl group) or a cyclohexylgroup.

In the alkoxycarbonyl group represented by X² in formula (I), the alkylmoiety may contain 1 to 6 carbon atoms, methyl and ethyl groups beingpreferred. Such groups are also preferred as substituents of themethylene group represented by Y¹ in formula (I).

Particularly valuable salts for medical purpose are those having apharmaceutically acceptable cation such as an alkali metal e.g. sodiumand potassium, an alkaline earth metal e.g. calcium and magnesium,ammonium or an organic base, particularly an amine such as ethanolamine.Salts having non-pharmaceutically acceptable cations are included withinthe ambit of this invention as useful intermediates for the productionof pharmaceutically acceptable salts, and of the acids or esters offormula (I).

Except when there is clear indication to the contrary, formula (I) andother formulae in the specification embrace all stereoisomersrepresented therein. In particular such formulae include theenantiomeric forms, racemates and diastereomers. Thus, for example, thecompounds of formula (I) contain an additional asymmetric carbon atomwhen Y¹ includes a hydroxyl group. The diastereomers arising from thisadditional asymmetric carbon atom may be separated in conventionalmanner, e.g. by column chromatography.

The compounds of formula (I) are of value in having pharmacologicalproperties related to those of natural prostaglandins; thus, thecompounds may mimic or antagonise the biological effects of members ofthe prostaglandin (PG) `A`, `B`, `C`, `D`, `E` and `F` series. Forexample, compounds of formula (I) have been found to mimic theanti-aggregatory effect of PGE₁ on blood platelets.

By reason of their prostaglandin-related properties, the compounds offormula (I) are useful in the pharmacological characterisation anddifferentiation of the biological activities of the naturalprostaglandins and their `receptors`. The further understanding of thephysiological role of prostaglandins is of course valuble in the searchfor new and improved therapeutic substances.

The compounds of formula (I) are also of value as therapeutic agents.The present invention therefore provides the above-defined compounds offormula (I) and their salts for use in a method of treatment of thehuman or animal body by therapy, particularly the treatment orprophylaxis of a thrombo-embolic disorder in a human or animal body. Itis to be understood that the term "thrombo-embolic disorder" includesthose disorders whose etiology is associated with platelet aggregation.

In particular compounds of formula (I) such as the preferred classes ofcompounds described above and especially 1β, 5β,7α-2-(3-cyclohexyl-3β-hydroxypropyl)-7-(3-carboxypropylthio)-2,4-diazabicyclo[3.3.0]octan-3-one,of formula ##STR3## have a potent anti-aggregatory effect on bloodplatelets and are useful whenever it is desired to inhibit plateletaggregation or to reduce the adhesive character of platelets, forexample in the treatment or prevention of the formation of thrombi inmammals, including man. The compounds are particularly useful in thetreatment and prevention of myocardial infarcts, thromboses, andstrokes. The compounds may also be used to promote patency of vasculargrafts following surgery, and to treat complications of arteriosclerosisand conditions such as atherosclerosis, blood clotting defects due tolipidemia, and other clinical conditions in which the underlyingaetiology is associated with lipid imbalance or hyperlipidemia. Afurther use for such compounds is as an additive to blood and otherfluids which are used in artificial extracorporeal circulation andperfusion of isolated body portions. The compounds of formula (I) mayalso be used in the treatment of peripheral vascular disease and angina.

In experiments which have been carried out on the rat, compounds offormula (I) have been shown to have a very low ore negligiblehypotensive effect which may be of advantage in clinical situationswhere a hypotensive or vasodilatory effect is undesirable.

Those compounds of formula (I) which mimic the effect of PGE₁ ofantagonising histamine-induced bronchoconstriction may be used in thetreatment or prophylaxis of bronchial asthma and bronchitis byalleviating the bronchoconstriction associated with this condition.

Compounds of formula (I) such as 1β, 5β,7α-(3-carboxypropylthio)-2-(3-hydroxyoctyl)-2,4-diazabicyclo[3.3.0]-octan-3-oneand 1β, 5β,7α-3-(cyclohexyl-3-hydroxypropyl)-7-(3-carboxypropylthio)-2,4-diazabicyclo/3.3.0/-octan-3-one,which inhibit pentagastrin-induced gastric acid secretion and reduce theformation of indomethacin-induced gastric lesions in rats are useful inreducing excessive gastric secretion, reducing and avoidinggastro-intestinal ulcer formation and accelerating the healing of suchulcers already present in the gastrointestinal tract whether such ulcersarise spontaneously or as a component of polyglandular adenomasyndromes.

In addition the compounds of formula (I) may be used in the treatment ofproliferative skin diseases such as are associated with excessive celldivision in the epidermis or dermis which may be accompanied byincomplete cell differentiation. Particular conditions which may bealleviated include psoriasis, atopic dermatitis, nonspecific dermatitis,primary irritant contact dermatitis, allergic contact dermatitis, basaland squamous cell carcinomas of the skin, lamellar icthyosis,epidermolytic hyperkeratosis, premalignant sun-induced keratosis,non-malignant keratosis, acne, and seborrheic dermatitis in humans andatopic dermatitis and mange in domestic animals. For the treatment ofthese conditions the compounds are desirably applied topically to theaffected skin. Alternatively they may be administered by an intradermalor intramuscular injection, for example directly into the skin lesion orinto the surrounding tissue. Injectable compositions will generallycontain from 0.1 to 0.5% w/v of active ingredient.

A further use for compounds of formula (I) which mimic the uterinesmooth muscle effects of PGE₂ and PGF₂α is as anti-fertility agents, inparticular as abortifacients.

The amount of a compound of formula (I) required to achieve the desiredbiological effect will of course depend on a number of factors, forexample, the specific compound chosen, the use for which it is intended,the mode of administration, and the recipient. In general, a daily dosemay be expected to lie in the range of from 1 μg to 20 mg per kilogrambodyweight. For example, an intravenous dose may lie in the range offrom 5 μg to 1 mg/kg which may conveniently be administered as aninfusion of from 0.01 to 50 μg per kilogram per minute. Infusion fluidssuitable for this purpose may contain from 0.001 to 100, for examplefrom 0.01 to 10 μg per milliliter, preferably 1 to 10 μg/ml. Unit dosesmay contain from 10 μg to 100 mg of a compound of formula (I), forexample, ampoules for injection may contain from 0.01 to 1 mg, andorally administrable unit dose formulations such as tablets or capsulesmay contain from 0.1 to 50, for example 2 to 20 mg. Such dosage unitsmay be administered for example, 1,2,3 or 4 times per day, separately orin multiples thereof.

More specifically, when a compound of formula (I) is used to inhibitplatelet aggregation it is generally desirable to achieve aconcentration in the appropriate liquid, whether it be the blood of apatient or a perfusion fluid, of about 1 μg to 10 mg, for example from10 μg to 1 mg, per liter.

The abovementioned doses refer to the acids, amides, ester and alcoholsof formula (I); where a salt is used, the dose should be taken asreferring to the corresponding anion.

According to a further feature of the present invention we providepharmaceutical formulations comprising, as active ingredient, at leastone compound of formula (I) and/or a pharmacologically acceptable saltthereof (as defined above) together with at least one pharmaceuticalcarrier or excipient. These pharmaceutical formulations may be used inthe treatment or prophylaxis of the conditions referred to above. Thecarrier must of course be `acceptable` in the sense of being compatiblewith the other ingredients of the formulation and not deleterious to therecipient thereof. The carrier may be a solid or a liquid, and ispreferably formulated with a compound of formula (I) as a unit-doseformulation, for example a tablet, which may contain from 0.05% to 95%by weight of the active ingredient. Other pharmacologically activesubstances may also be present in formulations of the present inventionfor example β-adrenoceptor blocking agent such as propranolol. Thecompound of formula (I) may be incorporated in the formulations eitherin the form of an acid or a salt or ester thereof, and the formulationsmay be prepared by any of the well-known techniques of pharmacyconsisting essentially of admixture of the components of theformulation.

The formulations include those suitable for oral, rectal, topical, (e.g.buccal such as sub-lingual) or parenteral (e.g. subcutaneous,intramuscular or intravenous) administration, although the most suitableroute in any given case will depend in the nature and severity of thecondition being treated, and on the nature of the active compound.

Formulations suitable for oral administration may be presented asdiscrete units such as capsules, cachets, lozenges or tablets eachcontaining a predetermined amount of the active compound; as powders orgranules; as solutions or suspensions in aqueous non-aqueous liquids; asoil-in-water emulsions; or as water-in-oil liquid emulsions,. Suchformulations may be prepared by any of the methods of pharmacy but allmethods include the step of bringing into association the activeingredient with the carrier which comprises one or more appropriateingredients. In general, the formulation may be prepared by uniformlyand intimately admixing the active ingredient with liquids or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation. For example a tablet may beprepared by compression or moulding a powder or granules of the activeingredient, optionally with one or more accessory ingredients.Compressed tablets may be prepared by compressing, in a suitablemachine, the active ingredient in a free-flowing form such as a powderor granules optionally mixed with a binder, lubricant, inert diluent,surface active or dispersing agent(s). Moulded tablets may be made bymoulding in a suitable machine the powdered active ingredient moistenedwith an inert liquid diluent.

Formulations suitable for buccal (e.g. sub-lingual) administrationinclude lozenges comprising the active ingredient compound in aflavoured bases, e.g. sucrose and acacia or tragacanth; and pastillescomprising the active ingredient in an inert base such as gelatin andglycerin; or sucrose and acacia.

Formulations of the present invention suitable for parenteraladministration conveniently comprise sterile aqueous preparations of theactive ingredient which preparations are preferably isotonic with theblood of the intended recipient. These preparations are preferablyadministered intravenously, although administration may also be effectedby means of subcutaneous or intrasmucular injection. Such preparationsmay be conveniently prepared by admixing the active ingredient withwater and rendering the product sterile and isotonic with the blood.

Formulations suitable for rectal administration are preferably presentedas unit-dose suppositories. These may be prepared by admixture of theactive ingredient with one or more conventional solid carriers, formingthe suppository base for example cocoa butter, and shaping of theresulting mixture.

Formulations suitable for topical application to the skin preferablytake the form of an ointment, cream, lotion, paste, gel, spray, aerosolor oil. Carriers which may be used in such formulations includepetroleum jelly, lanolin, polyethylene glycols, alcohols andcombinations thereof. The active ingredient is generally present in aconcentration of from 0.1 to 15% w/w of the composition, for examplefrom about 0.5 to about 2%.

According to a still further feature of the present invention we providea process for the preparation of compounds of formula (I) and saltsthereof which comprise reacting a compound of formula

    X.sup.2 -X.sup.1 -X-H                                      (II)

(wherein X, X¹, and X² are as hereinbefore defined) or a functionalequivalent thereof with a compound of formula ##STR4## (wherein Z, Y andY² are as defined above and Y^(1a) has the meanings given above for Y¹with the additional possibilities that it may also represent a methylenegroup substituted by a protected hydroxy group or by an alkyl group anda protected hydroxy group and A represents a leaving group in the α- orβ-configuration which is displaceable by the compound of formula (II)e.g. a hydrocarbon sulphonyloxy group, such as a p-toluenesulphonyloxyor methanesulphonyloxy group, or a halogen atom such as a chlorine atom)and subsequently if desired, removing any hydroxy protecting group whichmay be present.

The compound of formula (II) may be conveniently employed in the form ofa salt, for example of formula

    X.sup.2 --X.sup.1 --X.sup.-- --M.sup.+

where M⁺ is an alkali metal, e.g. sodium cation. The salt may beprepared by treatment of a compound of formula (II) with an alkali metalalkoxide such as sodium methoxide. The salt may alternatively beprepared from the corresponding lactone particularly when the group X¹represents a C₃₋₄ alkylene group.

The reaction of the compound of formula (II) or a functional equivalentthereof with the compound of formula (III) is advantageously effected ina polar organic solvent medium, e.g. dimethylsulphoxide or an amidesolvent such as dimethylformamide, conveniently at ambient temperature.

When using the above process to prepare a compound of formula (I) inwhich the group X is in the α-configuration a compound of formula (II)in which the leaving group A is in the β-configuration should be used.Similarly, with a compound of formula (I) in which X is in theβ-configuration, a starting material of formula (III) in which theleaving group A is in the β-configuration will be required. The latterstarting materials may be prepared from a corresponding startingmaterial of formula (III) containing a different leaving group in theβ-configuration by reacting the latter material with a suitable reagentserving to replace the first leaving group (in the β-configuration) witha second (desired) leaving group (in the α-configuration). Thus, forexample, a compound of formula (III) in which A represents a halogenatom in the β-configuration may be prepared by reaction of acorresponding compound of formula (III) in which A represents ahydrocarbon sulphonyloxy group in the β-configuration with anappropriate source of halide anions e.g. an alkali metal halide such aslithium chloride.

The compounds of formula (III) wherein A represents a leaving group inthe β-configuration may be prepared for example by reacting a compoundof formula ##STR5## (wherein Z, Y, Y^(1a) and Y² are as hereinbeforedefined) with an appropriate reagent serving to introduce the group A inthe β-configuration. Thus, for example, a compound of formula (IV) maybe reacted with a hydrocarbon sulphonyl halide (e.g. chloride) tointroduce a hydrocarbon sulphonyl group. The reaction is convenientlyeffected in the presence of an organic base such as pyridine.

The compounds of formula (IV) may be prepared for example by reacting acompound of formula ##STR6## (wherein Z, Y, Y^(1a) and Y² are ashereinbefore defined) with an appropriate reducing agent for example ametal borohydride or substituted borohydride, particularly sodiumborohydride.

The present invention provides compounds of the general formula ##STR7##wherein Z is as hereinbefore defined and W represents a hydrogen atom ora group of formula

    Y--Y.sup.1a --Y.sup.2a --Y.sup.3a

wherein Y and Y^(1a) are as hereinbefore defined, Y^(2a) represents acovalent bond or straight or branched alkylene group having 1 to 7carbon atoms optionally substituted in the carbon adjacent Y^(1a) by oneor two groups each of which may be alkyl or a cyclic radical;

Y^(3a) represents hydrogen, hydroxy, alkoxy of 1 to 7, preferably 1 to4, carbon atoms, a cyclic radical, phenyl, benzyl, phenoxy or benzyloxy,wherein each of phenyl, benzyl, phenoxy and benzyloxy may be substitutedin the benzene ring by one or more groups selected from hydroxy,halogeno, nitro, amino, acylamino, alkenyl, alkoxy, phenyl and alkylwhich may itself be substituted by one or more halogeno groups; orY^(2a) and Y^(3a) together form an alkyl group of 1 to 7 carbon atomshaving at least one hydrogen replaced by fluoro;

or Y is a bond, --CH₂ -- or --CH₂.CH₂ -- and Y^(1a), Y^(2a) and Y^(3a)taken together form a cycloalkyl or bicycloalkyl group substituted by ahydroxyl group which preferably has three carbon atoms separating itfrom the hydantoin ring.

In the definitions of Y^(2a) and Y^(3a) in formula (Va) the term cyclicradical means the monovalent radical derived by loss of a ring hydrogenatom from a monocyclic or polycyclic compound having from 3 to 12 ringatoms selected from carbon, nitrogen, oxygen and sulphur, which compoundmay be saturated or unsaturated and may be further substituted by one ormore alkyl groups, but excluding phenyl. Such cyclic radicals includecycloalkyl radicals having 3 to 10 carbon atoms such as cyclopropyl,cyclopentyl, cyclohexyl and cyclooctyl, bicycloalkyl radicals having 4to 10 carbon atoms such as adamantyl or norbornanyl(bicyclo[2,2,1]heptyl), spiroalkanyl radicals having 5 to 12 carbonatoms such as 2-spiro[3,3]heptyl,1-spiro[4,4]nonane and8-spiro[4,5]decane, cycloalkenyl radicals having 4 to 10 carbon atomssuch as 4-cyclopentene, heterocyclic radicals such as tetrahydrofuranyland tetrahydropyranyl and heteroaryl radicals such as thienyl, furyl,pyridyl, pyrimidyl, thiazolyl, imidazolyl and diazepinyl. Included inthe term cyclic radical are these wherein one or more hydrogen atoms arereplaced by fluoro.

The compounds of formula (VA) are useful as intermediates or startingmaterials for the preparation of a wide variety of prostaglandinanalogues and other compounds of related structure. Among theprostaglandin analogues which may be prepared from the compounds offormula (VA) are compounds of formula ##STR8## (wherein X, X¹, X², Y,Y^(1a), Y^(2a), Y^(3a), and Z are as hereinbefore defined), suchcompounds including the particular class of compounds represented byformula (I) above. These compounds of formula (IA) comprise compoundswhich generally have the broad profile of pharmacological propertiesdescribed above for the compound of formula (I) and which may beprepared in an analogous manner to the latter compounds.

The compounds of formula (VA) may be prepared from compounds of formula##STR9## (wherein W and Z are as hereinbefore defined and Q represents aketone protecting group, e.g. an ethylenedioxy group) by cyclisationunder aqueous acidic conditions, for example, using a strong acid. Thisreaction conveniently results in the deprotection of the ketone group inthe cyclopentane ring and the concomitant cyclisation of theheterocyclic ring. The reaction may be effected, if desired, in thepresence of an inert solvent for example a hydrocarbon solvent such aspetrol or more preferably an ether solvent such as tetrahydrofuran.

Compounds of formula (IV) may be prepared for example by reaction of acompound of formula ##STR10## (wherein Q and W are as defined above)with cyanic acid or an alkyl isocyanate depending respectively onwhether Z in formula (VA) is hydrogen or alkyl.

When cyanic acid is used, it is conveniently produced in situ by the useof an alkali metal cyanate, e.g. potassium cyanate, and an acid, e.g. anequivalent amount of mineral acid which may be added to the reactionmedium; desirably an inert solvent is present which is preferably polarsuch as water or a mixture of water with acetone, dimethylformamide,dimethylsulphoxide or a lower alkanol such as ethanol. Alternatively thesolvent may be a hydrocarbon, an ether or halogenated hydrocarbon suchas chloroform. Where desired, the reaction may be promoted by heatingthe reactants.

Similar reaction conditions may be used when an alkyl isocyanate is usedexcept that it is unnecessary to provide an equivalent amount of acid,as an acid addition salt or otherwise, in the reactants.

Instead of using a cyanate or isocyanate, a compound of formula (VII)may be reacted with for example, urethane, urea, nitrourea or anN-alkylurea. A solvent is not essential but if desired an inert solventmay be used such as one mentioned above for the reaction of the compoundof formula (VII) with cyanic acid. The reaction is preferably effectedat an elevated temperature, for example from 100° to 125° C. buttemperatures of up to 150° C. may be employed.

In the above described synthesis, the intermediate of formula (VI) neednot be isolated from the reaction mixture and may be converted directlyto compounds of formula (VA) under the described reaction conditions.

Compounds of formula (VII) wherein W represents a group of formula--Y--Y^(1a) --Y^(2a) --Y^(3a) (wherein Y, Y^(1a), Y^(2a) and Y^(3a) areas hereinbefore defined) may be prepared for example by reacting acompound of formula (VIII) with a compound of formula (IX): ##STR11##(wherein Q, Y, Y^(1a), Y^(2a) and Y^(3a) are as hereinbefore defined,one of T¹ and T² is amino and the other is halo (preferably bromo) orsulphonyloxy. The reaction is preferably effected in a solvent medium,e.g. a hydrocarbon solvent such as toluene.

The intermediates of formula (VII) wherein W is -Y-Y^(1a) -Y^(2a)-Y^(3a) when Y^(1a) is carbonyl may also be prepared by reaction of anamine of formula (VIII) wherein T¹ is amino with an unsaturated ketoneof formula

    CR.sub.2 =CH.CO.Y.sup.2a.Y.sup.3a                          (X)

wherein Y^(2a) and Y^(3a) have the same meaning as in formula (VII) andR is as defined in the definition of Y in formula (I); the reactionbeing effected in the presence or absence of an inert solvent, and atroom temperature or optionally with heating.

Compounds of formula (VIII) may be prepared from cyclopent-2-enone inconventional manner, for example according to the method of DePuy (J.Org. Chem., 1964, 29, 3508) in the case of the preparation of5-bromo-3,3-ethylenedioxycyclopentene. Compounds of formula (VIII)wherein T¹ is amino may be prepared from compounds of formula (VIII)wherein T¹ is halo, e.g. bromo, by reaction with sodium azide andsubsequent catalytic reduction.

The present invention also provides an alternative process for thepreparation of compounds of formula (I) and the above-identified saltswhich comprises reacting a compound of formula ##STR12## (wherein X, X¹,X² and Z are as defined above) with a compound of formula

    Hal--Y--Y.sup.1a --Y.sup.2                                 (XII)

(wherein Y, Y^(1a) and Y² are as hereinbefore defined and Hal is a haloradical preferably bromo) and subsequently, if desired, removing anyhydroxy protecting group which may be present. The reaction may beeffected by formation of a salt of a compound of formula (XI), e.g. bytreatment with sodium hydride in an inert solvent and subsequentreaction with the compound of formula (XII).

The compounds of formula (I) wherein Y^(1a) is carbonyl mayalternatively be prepared by reaction of a compound of formula (XI) witha compound of formula (X) as defined above.

The compound of formula (XI) employed as starting material in theabove-described process may be prepared from a compound of formula (VII)wherein W represents a hydrogen atom using the same general procedurespreviously described for the preparation of compounds of formula (I),(III) and (IV)

Compounds of formula (VA) wherein Z and W both represent hydrogen atomsare useful as intermediates in the preparation of analogues of biotin.

In the preparation of compounds of formula (I) and intermediatestherefor, it may be desirable to protect any labile hydroxy grouppresent in the molecule by the use of an appropriate protecting group.Such protecting groups are well-known in the art and include acyl (e.g.C₁₋₆ alkanoyl such as acetyl or aroyl), tetrahydropyran-2-yl,1-ethoxyethyl, aralkyl such as benzyl, and silyl (e.g. trialkylsilylsuch as trimethylsilyl).

Removal of protecting groups may be carried out by appropriate methodsknown to those skilled in the art. For example, an acyl group may beremoved by acid or base hydrolysis and a benzyl group by reductivecleavage, e.g. by hydrogenolysis using for example a palladium/charcoalcatalyst.

In the preparation of compounds of formula (I) the hydroxy group presentin the hydroxymethylene group which may be represented by Y^(1a) informulae (III), (IV) and (V) is preferably protected using an acetylprotecting group, which may be conveniently introduced by reacting anappropriate compound of formula (V) with an acetylating agent such asacetic anhydride. The acetyl protecting group may be removed, forexample, after reaction of the compounds of formula (II) and (III), e.g.by base hydrolysis.

Another instance where protection of a hydroxy group may be desirable isin the reaction of a compound of formula (VIII) with a compound offormula (IX) where any hydroxy group in Y^(1a) of the latter compound isdesirably protected, for example by an aralkyl group such as a benzylgroup. This protecting group may be subsequently removed at a laterconvenient stage in the synthesis, for example, after the cyclisation ofthe compound of formula (VI) to form a compound of formula (VA).

It will be appreciated that a compound of formula (I) wherein Y¹ iscarbonyl may be converted to the corresponding secondary alcohol byreduction with a suitable reducing agent, such as sodium borohydride.Also, an alcohol of formula (I) wherein Y¹ is --CH.OH-- may be oxidisedto the corresponding ketone using Jones' reagent, acid dichromate or anyother suitable reagent.

The alcohols of formula (I) wherein X² is hydroxymethylene may also beobtained by reduction with an appropriate reducing agent of thecorresponding acid, ester, acid halide, acid anhydride or aldehyde. Theappropriate reducing agent will depend on the particular substrate, buta reactant which may in general be used is lithium borohydride. Inparticular a carboxylic acid may for example be converted to acorresponding mixed anhydride with ethylchloroformate in the presence ofa base such as triethylamine, and subsequently reduced to the alcoholusing sodium borohydride. Similarly an ester may be reduced to thealcohol using di-iso-butyl aluminium hydride in an inert solvent such asether or hydrocarbon such as hexane or benzene. Such alcohols may alsobe prepared by catalytic hydrogenation.

Alternatively the alcohols of formula (I) wherein X² is hydroxymethylenemay be prepared by hydrolysis of a corresponding halide with anappropriate reagent. For this purpose a hydroxide may be used forexample an aqueous alkali or a suspension of silver oxide in water.

The salts of compounds of formula (I) wherein X² is carboxyl and/or Z ishydrogen may be prepared in conventional manner.

The following Examples illustrate the present invention.

PREPARATION 1 2-cis-, 2-trans-3-Cyclohexylacrylonitrile

A suspension of sodium hydride (100%, 10.93 g) in dryN,N-dimethylformamide (DMF) (230 ml) was stirred vigorously under drynitrogen and diethyl cyanomethylphosphonate (81,00 g) in dry DMF (65 ml)was added dropwise. After the addition was complete, the mixture washeated at 80° until gas evolution ceased. The solution was cooled andcyclohexanecarboxaldehyde (51.10 g) was added dropwise at 30°. Theresulting solution was stirred at room temperature for 1 hr then dilutedwith water and the product extracted into n-pentane. The combinedorganic extracts were washed with water, dried (MgSO₄), the solventremoved in vacuo, and the residual oil distilled, giving a mixture of2-cis- and -2-trans-3-cyclohexylacrylonitrile as a colourless oil, b.p.53°-60°/0.8 mm.

PREPARATION 2 3-Benzyloxy-3-cyclohexylpropylamine

The foregoing mixture of 2-cis and 2-trans-3-cyclohexylacrylonitrile(26.50 g) was dissolved in sodium benzylate solution prepared fromsodium (0.65 g) and benzyl alcohol (90 ml) and the resulting solutionheated on the steam-bath with stirring for 4 hours then set aside atroom temperature for 18 hours. The resulting dark solution was dilutedwith ether and washed with water. The ethereal extract was dried (Na₂SO₄), the solvent removed in vacuo, and the residue unchanged nitrileremoved by distillation under high vacuum. The residual material wastaken up in ether, decolorised with activated charcoal, filtered, andthe solvent removed in vacuo. The residual yellow syrup (ca. 22 g) wasdissolved in dry ether (40 ml) and added dropwise at +5° to a stirredsuspension of lithium aluminium hydride (3.4 g) in dry ether (125 ml).After 1 hour at room temperature, the reaction mixture was treated withwater and the resulting gel filtered through Celite. The yellow organicphase was separated, dried (MgSO₄), the solvent removed in vacuo, andthe residual orange oil distilled, giving3-benzyloxy-3-cyclohexylpropylamine as a colourless viscous oil, b.p.120°-5°/0.05-0.06 mm.

EXAMPLE 1 N-(3-Benzyloxyoctyl)-4,4-ethylenedioxycyclopent-2-enamine

5-Bromo-3,3-ethylenedioxycyclopentene was prepared fromcyclopent-2-enone (5.0 g) by the method of DePuy (J. Org. Chem., 1964,29, 3508) and dissolved in dry toluene (50 ml). The solution was addeddropwise with stirring to 3-benzyloxyoctan-1-amine (9.48 g) in drytoluene (40 ml) at -25°. The brown solution was stirred for 26 hr atroom temperature then at 40°L for 3.5 hour then triethylamine (6.0 g)was added. The resulting cloudy solution was washed with three portionsof water, then dried (MgSO₄) and the solvent evaporated in vacuo givinga red oil. Purification by column chromatography (silica, 100:7chloroform:methanol) gave the mixture of diastereomers ofN-(3-benzyloxyoctyl)-4,4-ethylenedioxycyclopent-2-enamine as a pale redoil, δ (CDCl₃) 0.88 (3H, bt, --CH₃), 3.92 (4H, s, --O--CH₂ --CH₂ --O--),4.50 (2H, s, --CH₂ --Ph), 7.31 (5H, bs, --Ph).

EXAMPLE 2N-(3-Benzyloxy-3-cyclohexylpropyl)-4,4-ethylenedioxycyclopent-2-enamine

The title compound was obtained from 3-benzyloxy-3-cyclohexylpropylaminein an analogous manner to that described in Example 1, δ (CDCl₃) 3.90(4H, s, --O--CH₂ CH₂ --O--), 4.53 (2H, s, --CH₂ Ph), 7.35 (5H, bs,--Ph).

EXAMPLE 32-(3-Benzyloxyoctyl)-cis-2,4-diazabicyclo-[3.3.0]octane-3,7-dione

N-(3-Benzyloxyoctyl)-4,4-ethylenedioxycyclopent-2-enamine (972 mg) inethanol (60 ml) was treated with potassium cyanate (360 mg) in water(4.0 ml) then 1,0 N aqueous hydrochoric acid (3.0 ml) at roomtemperature. After 18 hours, the mixture was diluted with water andextracted with chloroform. The extract was dried then decolourised andthe solvent was removed in vacuo to give crudeN-(3-benzyloxyoctyl)-N-(4,4-ethylenedioxycyclopent-2-enyl)urea as ayellow glass. This material was dissolved in tetrahydrofuran (11.0 ml)and 2.0 N aqueous hydrochloric acid (11.0 ml) and the solution set asideat room temperature for 1.25 hours. After dilution with water, theproduct was extracted into chloroform, and the solvent removed from thedried extract to give the mixture of diastereomers of2-(3-benzyloxyoctyl)-cis-2,4-diazabicyclo[3.3.0]octane-3,7-dione as acolourless glass, δ (CDCl₃) 0.95 (3H, bt, --CH₃), 2.41 ##STR13## 3.40(2H, m, --N--CH₂ --), 4.24 (2H, m, 1-H, 5-H), 4.48 and 4.50 (total 2H,both s, --CH₂ Ph from each isomer), 7.31 (5H, bs, --Ph).

EXAMPLE 42-(3-Benzyloxy-3-cyclohexylpropyl)-cis-2,4-diazabicyclo[3.3.0]octane-3,7-dione

The title compound was prepared fromN-(3-benzyloxy-3-cyclohexylpropyl)-4,4-ethylenedioxycyclopent-2-enaminein an analogous manner to that described in Example 3 δ (CDCl₃), 2.45##STR14## 4.30 (2H, m, 1-H, 5-H), 4.50 and 4.55 (total 2H, both s, --CH₂Ph from each isomer), 7.32 (5H, bs, --Ph).

EXAMPLE 5 2-(3-Hydroxyoctyl)-cis-2,4-diazabicyclo[3.3.0]octane-3,7-dione

2-(3-Benzyloxyoctyl)-cis-2,4-diazabicyclo[3.3.0]octane-3,7-dione (5.0 g)and 5% palladium on charcoal (1.5 g) in absolute ethanol (100 ml) werehydrogenated at room temperature and one atmosphere for 2 hours. Thesuspension was filtered through a pad of Celite and the residue washedwith chloroform and the combined organic phases concentrated in vacuo.The residual gum was purified by column chromatography (silica gel;eluted with 12% methanol, 58% ether 30% dichloromethane) giving twodiastereomeric products:

Less Polar Isomer, m.p. 55°-6° (from ether/n-hexane)

More Polar Isomer, m.p. 83°-4° (from ether/n-hexane/chloroform)

EXAMPLE 62-(3-Cyclohexyl-3-hydroxypropyl)-cis-2,4-diazabicyclo[3.3.0]octane-3,7-dione

The title compound was obtained as a mixture of diastereomers in ananalogous manner to that described in Example 5. The material obtainedwas used for subsequent reactions without separation into the twocomponent isomers.

EXAMPLE 7 2-(3-Acetoxyoctyl)-cis-2,4-diazabicyclo/3.3.0/octane-3,7-dione

2-(3-Hydroxyoctyl-cis-2,4-diazabicyclo[3.3.0]octane-3,7-dione (1.61 g)(more polar isomer) was dissolved in pyridine (6.0 ml) and aceticanhydride (6.0 ml) and set aside at room temperature for 18 hours. Thesolution was diluted with chloroform and washed with water, Nhydrochloric acid, aqueous sodium bicarbonate solution, then finallywater, then dried (MgSO₄) and the solvent removed in vacuo. The residualglass was recrystallized from chloroform/ether to give2-(3-acetoxyoctyl)-cis-2,4-diazabicyclo[3.3.0]octane-3,7-dione ascolourless needles m.p. 85°-6° (Rf 0.50, silica 6:3:1ether:dichloromethane:methanol).

The acetate of the less polar alcohol was prepared in a similar manner,m.p. 92°-3° (Rf 0.45, silica, 6:3:1:ether:dichloromethane:methanol).

EXAMPLE 82-(3-Acetoxy-3-cyclohexylpropyl)-cis-2,4-diazabicyclo[3.3.0]octane-3,7-dione

The title compound was obtained as a mixture of diastereomers in ananalogous manner to that described in Example 7.

EXAMPLE 91β,5β,7α-2-(3-Acetoxyoctyl)-7-hydroxy-2,4-diazabicyclo[3.3.0]octan-3-one

2-(3-Acetoxyoctyl)-cis-2,4-diazabicyclo[3.3.0]octane-3,7-dione (400 mg)(Isomer of m.p. 85°-6°) in ethanol (16 ml) was treated at +5° withsodium borohydride (52 mg) with stirring. After 4 hours at roomtemperature, excess ethanol was removed in vacuo and the residue dilutedwith water and the product extracted into ether. The extract was dried(MgSO₄), the solvent removed in vacuo, and the residue recrystallizedfrom ether/hexane giving1β,5β,7α-2-(3-acetoxyoctyl)-7-hydroxy-2,4-diazabicyclo[3.3.0]octan-3-oneas colourless crystals, m.p. 63°-4°.

The isomer of m.p. 92°-3° was similarly reduced giving colourlessneedles of m.p. 74°-5°.

EXAMPLE 101β,5β,7α-2-(3-Acetoxy-3-cyclohexylpropyl)-7-hydroxy-2,4-diazabicyclo[3.3.0]octan-3-one

The title compound was obtained as a mixture of diastereomers in ananalogous manner to that described in Example 9.

EXAMPLE 111β,5β,7α-2-(3-Acetoxyoctyl)-7-(4-methylphenylsulphonyloxy)-2,4-diazabicylo-[3.3.0]octan-3-one

1β,5β,7α-2-(3-Acetoxyoctyl)-7-hydroxy-2,4-diazabicyclo[3.3.0]octan-3-one(312 m) (Isomer of m.p. 63°-4°) in dry pyridine (2.4 ml) was treated atroom temperature with p-toluenesulphonyl chloride (240 mg). The orangesolution was set aside at room temperature for 24 hr then diluted withchloroform and washed with excess 2 N hydrochloric acid. The organicextract was dried (MgSO₄) and the solvent removed in vacuo and theresidual gum purified by column chromatography (silica, elution with23:2 ether:methanol) giving1β,5β,7α-2-(3-acetoxyoctyl)-7-(4-methylphenylsulphonyloxy)-2,4-diazabicyclo/3.3.0/octan-3-oneas colourless crystals, m.p. 59°-60° (from ether:hexane).

The isomer of m.p. 74°-5° was similarly converted into thep-toluenesulphonate as colourless plates, m.p. 51°-2° (fromether:hexane).

EXAMPLE 121β,5β,7α-2-(3-Acetoxy-3-cyclohexylpropyl)-7-(4-methylphenylsulphonyloxy)-2,4-diazabicyclo[3.3.0]octan-3-one

The title compound was obtained as a mixture of diastereomers in ananalogous manner to that described in Example 11.

EXAMPLE 131β,5β,7α-2-(3-Acetoxyoctyl)-7-(3-methoxycarbonylpropylthio)-2,4-diazabicyclo[3.3.0]octan-3-one

-Thiobutyrolactone (510 mg) was dissolved in methanolic sodium methoxide[from sodium (120 mg and dry methanol (10.0 ml)] and set aside at roomtemperature for 2 hours. The solvent was removed in vacuo and theresidue dissolved in dry dimethyl-sulphoxide (10.0 ml).1β,5β,7α-2-(3-Acetoxyoctyl)-7-(4-methylphenylsulphonyloxy)-2,4-diazabicyclo[3.3.0]octan-3-one(1.20 g) (isomer of m.p. 59°-60°) in dimethylsulphoxide (4.0 ml) wasadded in one portion to the thiolate solution (6.2 ml) prepared aboveand the mixture set aside at room temperature for 18 hours. The solutionwas then diluted with 0.5% aqueous sodium dihydrogen phosphate solution(150 ml) and the product extracted into ethyl acetate. The extract waswashed with water, dried (MgSO₄), the solvent removed in vacuo and theproduct purified by column chromatography (silica, elution with 3:100methanol:ether) giving1β,5β,7α-2-(3-Acetoxyoctyl)-7-(3-methoxycarbonylpropylthio)-2,4-diazabicyclo[3.3.0]octan-3-one as a colourless glass, (CDCl₃) 0.87 (3H, bt, --CH₂ --CH₃), 2.04(3H, s, --C--CH₃), 2.3 (2H, m, --CH₂ --CO₂ Me), 2.5 (2H, m, --CH₂--S--), 3.67 (3H, s, --O--CH₃), 4.25 (2H, m, 1-H, 5-H) (Rf 0.50, silica,1:20 methanol:ether). From1β,5β,7α-2-(3-acetoxyoctyl)-7-(3-methylphenylsulphonyloxy)-2,4-diazabicyclo[3.3.0]octan-3-oneof m.p. 74°-5° was similarly obtained the other isomer, δ (CDCl₃) 0.86(3H, bt, --CH₂ CH₃), 2.03 (3H, s, --CO--CH₃), 2.3 (2H, m, --CH₂ CO₂ Me),2.5 (2H, m, --CH₂ --S--), 3.66 (3H, s, --O--CH₃ ) and 4.19 (2H, m, 1-H,5-H). (Rf 0.40, silica, 1:20 methanol ether).

EXAMPLE 141β,5β,7α-2-(Acetoxy-3-cyclohexyl)propyl-7-(3-methoxy-carbonylpropylthio-2,4-diazabicyclo[3.3.0]octan-3-one

The title compound was obtained as a mixture of diastereomers in ananalogous manner to that described in Example 13.

EXAMPLE 151β,5β,7α-7-(3-carboxypropylthio)-2-(3-hydroxyoctyl)-2,4-diazabicycloz[3.3.0]-octan-3-one

1β,5β,7α-2-(3-Acetoxyoctyl)-7-(3-methoxycarbonylpropythio)-2,4-diazabicyclo[3.3.0]octan-3-one(830 mg) (Isomer of Rf 0.40, silica, 1:20 methanol:ether) in methanol(8.5 ml) was treated with 2 N aqueous sodium hydroxide (5.2. ml) and setaside at room temperature for 1.5 hours. The solution was diluted withwater, washed with ether, and the aqueous phase acidified to pH 3 withdilute hydrochloric acid. The product was extracted into chloroform, theextract dried (MgSO₄), the solvent removed in vacuo and the residuerecrystallized from chloroform:ether giving the more polar isomer of1β,5β,7α-7-(3-carboxypropylthio)-2-(3-hydroxyoctyl)-2,4-diazabicyclo[3.3.0]octan-3-oneas colourless prisms, m.p. 74°-5° (Compound No. 1).

From the ester of Rf 0.50 (silica, 1:20 methanol:ether) was similarlyobtained the less polar isomer of1β,5β,7α-7-(3-carboxypropylthio)-2-(3-hydroxyoctyl)-2,4-diazabicyclo[3.3.0]octan-3-oneas colourless prisms, m.p. 79°-80° (Compound No. 2).

EXAMPLE 161β,5β,7α-7-(3-Carboxypropylthio)-2-(3-hydroxy-3-cyclohexylpropyl)-2,4-diazabicyclo[3.3.0]octan-3-one

The title compound was obtained as a mixture of diastereomers in ananalogous manner to that described in Example 15.

The isomers were separated by preparative T.L.C. giving:

Less Polar Isomer, as colourless crystals, m.p. 148°-149.5° δ (CDCl₃)2.46 (2H, m, --CH₂ CO₂ H), 2.64 (2H, m, --CH₂ --S--), 3.3 (1H, m,CH--O--), 4.18 (2H, m, 1-H, 5-H), 6.1 (3H, b OH, --NH --CO₂ H).(Compound No. 3).

More Polar Isomer, as a colourless glass, δ (CDCl₃) 2.4 (2H, m, --CH₂--CO₂ H), 2.6 (2H, m, --CH₂ --S--), 3.3 (1H, m, --CH--OH), 4.2 (2H, m,1-H, 5-H); m/e 384 (C₁₉ H₃₂ N₂ O₄ S requires m/e 384) (Compound No. 4).

The following Examples illustrate pharmaceutical compositions accordingto the present invention wherein the "active ingredient" is a compoundof formula (I) as defined above, e.g. especially1β,5β,7α-2-(3-cyclohexyl-3α-hydroxypropyl)-7-(3-carboxypropylthio)-2,4-diazabicyclo[3.3.0]octan-3-one.

EXAMPLE A

    ______________________________________                                        Tablet                  In one tablet                                         ______________________________________                                        Active ingredient        5.0 mg                                               Lactose B.P.            82.0 mg                                               Starch B.P.             10.0 mg                                               Povidone B.P.C. (polyvinylpyrrolidone                                                                  2.0 mg                                               Magnesium Stearate       1.0 mg                                               ______________________________________                                    

Mix together the active ingredient, lactose and starch. Granulate thepowders using a solution of the povidone in Purified Water. Dry thegranules, and the Magnesium Stearate and compress to produce tablets,100 mg per tablet.

EXAMPLE B

    ______________________________________                                        Capsule              In one capsule                                           ______________________________________                                        Active ingredient    10 mg                                                    Lactose              79 mg                                                    Starch               10 mg                                                    Magnesium Stearate    1 mg                                                    ______________________________________                                    

Mix the powders in a powder blender, fill into hard gelatin capsules,100 mg per capsule.

EXAMPLE C

    ______________________________________                                        1 μg/ml Injection                                                          ______________________________________                                        Active ingredient      100 μg                                              Water for Injection    to 100 ml                                              ______________________________________                                    

Dissolve the active ingredient in the Water for Injection. Sterilise thesolution by filtration through a membrane filter, 0.22 um pore size,collecting the filtrate in a sterile receiver. Under aseptic conditions,fill the solution into sterile glass ampoules, 1 ml per ampoule. Seal byfusion of the glass.

EXAMPLE D

    ______________________________________                                        10 μg/ml Injection                                                         ______________________________________                                        Active ingredient      1 mg                                                   Ethyl Alcohol          10 ml                                                  Propylene Glycol       30 ml                                                  Water for Injection    to 100 ml                                              ______________________________________                                    

Dissolve the active ingredient in the Ethyl Alcohol, add the PropyleneGlycol and dilute to volume with Water for Injection.

Sterilise the solution by filtrate through a membrane filter, 0.22 μmpore size, collecting the filtrate in a sterile vessel. Under aspeticconditions, fill the solution into sterile glass vials, 10 ml per vial.Close with a sterile rubber plug and secure with an aluminium collar.

BIOLOGICAL ACTIVITY Cardiovascular effects in rats

Male normotensive rats Wistar (Charles River) strain, (250-350 g) wereanesthetised (chloroform) prior to cannulation of the left femoral veinand anaesthesia maintained by intravenous chloralose (60 mg/kg).Pulsatile blood pressure was recorded from the left femoral artery withan electronic transducer (Bell and Howell Type 4-327 L221) andintegrated heart rate was measured with a cardiotachometer triggeredfrom the arterial pressure waves.

The test compound was administered as a solution in physiological salineby intravenous injection via the femoral cannula. The responses recordedwere allowed to return to the preinjection levels between successiveadministrations.

Injections of the vehical alone in volumes equivalent to thosecontaining drug did not produce hypotension.

Compounds Nos. 1, 2, 3 and 4 were each found to have a hypotensiveeffect of less than 0.001-times that of prostacyclin as a standard.

Inhibition of Platelet Aggregation

Aggregation of platelets in 1 ml. of fresh human platelet rich plasma(PRP) was monitored in a Born aggregometer.

The compound to be tested was added to the PRP, and the resultingmixture incubated at 37° C. for 1 minute after which plateletaggregation was stimulated by the addition of adenosine diphosphate(ADP) to a concentration of 5 uM.

The anti-aggregatory effect of the compound was assessed by measuringthe percentage inhibition of platelet aggregation in the presence of thecompound as compared when it was completely absent.

The following relative potencies were found with respect to PGE₁ as astandard: Compound No. 1, 0.06x; Compound No. 3, 9x and 10.5x; CompoundNo. 4; 0.05x.

Anti-ulcer Activity

Compounds Nos. 1 and 3 were found to have respectively 0.50 and0.65-times the potency of PGE₂ for the reduction of indomethacin-inducedgastric ulceration in the rat.

We claim:
 1. A compound of the formula ##STR15## wherein X represents asulphur atom (--S--) or oxygen atom (--O--) in the α orβ-configuration;X¹ represents a C₁₋₅ straight chain or branched alkylenegroup or C₃₋₅ straight chain or branched alkenylene group; Z representsa hydrogen atom or a C₁₋₄ straight chain or branched alkyl group; Yrepresents a group of formula --CR₂ --CH₂ -- in which each R isindependently selected from hydrogen and methyl; Y¹ represents amethylene group substituted by hydroxyl, a methylene group substitutedby hydroxyl and C₁₋₆ alkyl, a methylene group or a carbonyl group; andY² represents a C₁₋₇ straight chain or branched alkyl group, phenyl,benzyl or a C₄₋₇ cycloalkyl; X² represents a carboxyl, carboxamide,hydroxymethylene, C₁₋₆ alkoxycarbonyl or 5-tetrazolyl group; or a saltof said compound of formula (1)when either X² is carboxyl, or Z ishydrogen or when X² is carboxyl and Z is hydrogen.
 2. A compound asclaimed in claim 1 wherein X represents a sulphur atom in theα-configuration.
 3. A compound as claimed in claim 1 or claim 2 whereinX² represents a carboxyl group.
 4. A compound as claimed in claim 1 or 2wherein Z represents a hydrogen atom.
 5. A compound as claimed in claims1 or 2 wherein Y¹ represents a methylene group substituted by hydroxylin the β-configuration.
 6. 1β, 5β,7α-2-(3-Cyclohexyl-3-β-hydroxypropyl)-7-(3-carboxypropylthio)-2,4-diazabicyclo[3.3.0.]octan-3-one,of formula ##STR16##
 7. An antithrombotic composition comprising aneffective antithrombotic amount of a compound of claim 1 or apharmaceutically acceptable salt thereof when either X² is carboxyl or Zis hydrogen, or X² is carboxyl and Z is hydrogen, together with at leastone pharmaceutical carrier or excipient.
 8. The composition of claim 7in which the active ingredient is1β,5β,7α-2-(3-cyclohexyl-3-β-hydroxypropyl)-7-(3-carboxypropylthio)-2,4-diazabicyclooctan-3-one.
 9. A method for the treatment or prophylaxis of athrombo-embolic disorder in a mammal which comprises administering tothe said mammal a compound of claim 1 or a pharmaceutically acceptablesalt thereof in an effective amount to treat or prevent said disorder.10. A method of reducing or preventing the undesired aggregation ofblood platelets in a mammal which comprises administering to said mammala compound of claim 1 or a pharmaceutically acceptable salt thereof inan effective amount to reduce or prevent the undesired aggregation ofblood platelets.
 11. The method of claim 9 in which the the compound is1β,6β,7α(-2-(3-cyclohexyl-3-β-hydroxypropyl)-7-(3-carboxypropylthio)-2,4-diazabicyclo[3.3.0]octan-3-one.12. The method of claim 10 in which the compound is 1β,5β,7α-2-(3-cyclohexyl-3-β-hydroxypropyl)-7-(3-carboxypropylthio)-2,4-diazabicyclo[3.3.0]octan-3-one.